The overarching goal of this application is to provide Dr. Jesse Mez, M.D., M.S. with additional training in the field of Alzheimer's disease (AD) genetics so that he may develop into an independent investigator and skilled future leader of a multidisciplinary research team. Dr. Mez, his mentors and the consultants on the application have designed a research plan and complementary training plan that will engage him in several new areas of study and provide him with the skills necessary for leading a research team with diverse expertise. Patients with AD can present with substantial variation in clinical presentation While a considerable number of genetic risk factors have been identified for the incidence of AD, few genetic risk factors have been identified for the variation in clinical presentation of AD. Genetic risk factors provide insight into underlying AD pathophysiology and offer potential targets for disease-modifying therapies. The research plan will focus on identifying genetic risk factors for the variation in neuropsychological profile of patients with AD. The major research aims of the application are 1) to identify common genetic variants associated with the difference between memory and non-memory function in AD using genome wide association (GWA), 2) to identify causal variants in genes implicated by the GWA in Aim 1 using whole exome sequencing (WES) data and 3) to identify A) gene x gene interactions among variants identified in aim 1 and variants previously found to be associated with incident AD and B) gene x environment interactions among variants identified in aim 1 and AD risk factors with environmental influences: education, hypertension and type 2 diabetes mellitus. The plan makes use of a large volume of genetic and neuropsychological data already obtained or in the process of being obtained through the AD Genetic Consortium, the National AD Sequencing Project, their associated parent studies and several additional studies. Sophisticated genetic and psychometric approaches will be employed to combine and analyze the datasets. The major training goals for Dr. Mez are 1) to develop proficiency in analyzing large-scale genetic data, especially WES data and 2) to learn and apply modern psychometric approaches, including item response theory, to analyze neuropsychological data. Dr. Mez is surrounded by a rich training environment at Boston University (BU). He is a member of the BU Alzheimer's Disease Center and is co-mentored by Dr. Neil Kowall, head of the center. He also is affiliated with the Biomedical Genetics Division in the Department of Medicine, headed by Dr. Lindsay Farrer, who serves as his primary mentor. Lastly he will receive training in psychometrics via frequent contact with Paul Crane, an expert in modern psychometric approaches, at the University of Washington, who will also serve as a co-mentor. The combination of Dr. Mez's current and growing expertise in dementia and the skills he will develop through this training grant will be rare for a clinician researcher, will greatly enhance his prospects for future R01 funding and will position him to lead a future multidisciplinary team focused on the genetics of dementing illnesses.